长期口服大环内酯类药物对慢性气流阻塞性肺疾病的作用

1、长期口服大环内酯类药物对慢性气流阻塞性肺疾病的作用北京大学人民医院 呼吸与危重症医学科马艳良Case -Lung Function实际值预测值舒张后实际值舒张后预测值FEV11.3648.231.6558.51FVC2.6276.832.7881.52FEV1/FVC51.90%59.35%Case -Clinical Historyn男性，28岁n间断咳嗽、咳痰2020年，喘憋5 5年n多在着凉后发作，秋冬多见，咳黄痰，偶有咯血n近5年出现活动后喘憋，受凉、遇刺激性气味时喘憋加重n鼻窦炎史，无吸烟史、饮酒史，无家族遗传病史n青霉素过敏n 体温：36.5 脉搏：74次/分 呼吸：18次/分 血

2、压：105/75mmHg n 全身浅表淋巴结无肿大，口唇红润，扁桃体无肿大n 气管位置居中，双肺叩诊清音，双肺可闻及粗大湿罗音n 余查体无异常Case -Physical Examination气流阻塞n诊断?nAsthmanCOPDnAsthma+COPDnOthers诊断：支气管扩张症气流阻塞n支气管哮喘nCOPDnACOSn支气管扩张症nDPBnBOnOthersl气道慢性炎症l细菌定植l反复急性加重大环内酯类抗炎作用v对炎症细胞的影响v可促进巨噬细胞和中性粒细胞的凋亡v可抑制肥大细胞释放炎症介质 v对炎性细胞因子的影响v抑制IL-10、6、8，INF-的释放，TNF-的产生 v对核转录

3、因子NF-B的影响 v抑制NF-B的表达，因此抑制炎性蛋白的表达并促进凋亡 其他作用v细胞保护作用：v与细胞膜磷脂作用，引起炎症细胞膜的流动性和电荷等生物物理性质改变，发挥膜稳定作用 v减少呼吸道分泌物的产生v抑制黏液分泌v抑制细菌生物被膜v利于-内酰胺类抗生素发挥抗菌作用。 大环内酯类治疗COPD双管齐下的作用机制抗菌作用和抗炎作用Yamaya M,et al.Eur Respir J.2012;40：485494.大环内酯类抗菌作用降低细菌负荷和细菌感染抗炎作用l 对凋亡中性粒细胞的吞噬作用l 降低机体的趋化作用l 降低促炎细胞因子的产生 l 降低黏附分子的表达 l 降低活性氧的产生降低C

4、OPD患者的慢性气管炎症和粘液的产生大环内酯类对铜绿假单胞菌(PA)具有多重抑制作用l 对PA的群体反应*的调节 阿奇霉素可在核糖体水平减少自诱导物生成，从而减少PA群体反应性顾晓花,等.中华结核和呼吸杂志.2006;29(3):200-202.大环内酯类 对PA的黏附、运动作用的抑制 大环内酯类药物抑制细菌鞭毛合成，抑制细菌游走，降低PA的致病能力 阿奇霉素比红霉素、罗红霉素铜绿假单胞菌鞭毛的抑制作用更明显 对PA的生物膜形成的抑制作用阿奇霉素能抑制PA生物膜形成 对PA毒素及其他代谢产物生成的抑制 大环内酯类尤其阿奇霉素，较明显抑制PA产生外毒素、弹性蛋白酶、蛋白酶、磷脂酶等物质*群体反应

5、是指细菌间的沟通现象，细菌都有信号传导的能力，由细菌的自诱导物引起，从而选择聚集、增值和释放毒素长期口服大环内酯类对慢性气流阻塞性疾病的作用DPB-Effects of macrolides on survivalAm J Respir Crit Care Med 1998;157:18291832Effects of prolonged use of azithromycin in patients with CFPulm Pharmacol Ther 2009;22:467472.FEV1 3.53%FEV1 4.66%疗程定植Long-term macrolide therapy in

6、COPD patients lA systematic literature search of PubMed and Embase before Oct 1, 2012Inclusion Criteria lRCT that enrolled patients with COPD in the stable stagel Drugs were administered orallyl Macrolide therapy lasted 2 weeksl clinical efficacy or safety was reported Respiration 2013;86:254260Clin

7、ical characteristics of the 6 trialsLiterature sourceTotal subjects (n)Treated subjects (n)FEV1, L/s at baselineControl groupMacrolides groupSuzuki et al. 2001109551.30 (0.08) 1.47 (0.15)Banerjee et al. 200567311.12(0.07)1.13 (0.07)Seemungal et al. 2008109531.36 (0.55) 1.27 (0.51)Blasi et al.2010221

8、1_He et al. 201036181.02(0.41)1.12(0.47)Albert et al. 201111425701.10(0.50)1.12(0.52)Clinical characteristics of the 6 trialsLiterature sourceTherapy strategyDose per weekConcomitant medicationCourseSuzuki et al. 2001Erythromycin 200-400mg/d vs riboflavin 10mg/d1400-2800mgTheophylline and anticholin

9、ergic agents, except CS12mBanerjee et al. 2005Clarithromycin 500mg/d vs placebo3500mgICS3mSeemungal et al. 2008Erythromycin 250mg/bid vs placebo3500mgICS12mBlasi et al.2010Azithromycin 500mg 3/w vs standard therapy1500mgNot mentioned6mHe et al. 2010Erythromycin 125mg tid vs placebo2625mgICS, theophy

10、lline,anticholinergic agents, -adrenergic agents6mAlbert et al. 2011Azithromycin 250 mg/d vs placebo1750mgICS, anticholinergic agents, -adrenergic agents12mRR for the frequency of AECOPD 大环内酯类治疗显著降低COPD患者急性加重的频率酯酯Which drug?How long?Subgroup analyses of the specific drug Exacerbation frequency of CO

11、PD No. of StudiesRR(95% CI)PErythromycin30.48 (0.24, 0.96)0.04Azithromycin20.65 (0.33, 1.29)0.22Clarithromycin12.90 (0.61, 13.93)0.18Proportion of Participants Free from Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) for 1 YearAzithromycin 250 mg/d PlaceboN Engl J Med 2011, 365:

12、689-698 N=114212msAlbert et al. 2011Subgroup analyses of the the observed periodExacerbation frequency of COPD No. of StudiesRR(95% CI)P3 ms12.90 (0.61, 13.93)0.186 ms20.56 (0.36, 0.87)0.00912 ms 30.59 (0.37, 0.95)0.03Side effects大环内酯类治疗增加非致死性不良反应Subgroup analyses Drug adverse effects No. of Studies

13、RR(95% CI)PErythromycin20.92 (0.21, 4.01)0.91Azithromycin22.03 (0.41, 10.12)0.39Clarithromycin12.90 (0.61, 13.93)0.18Placebo31.30 (1.05, 1.61)0.02Non-placebo25.51 (0.67, 45.28)0.113 ms12.90 (0.61, 13.93)0.186 ms21.94 (0.14, 26.69)0.6212 ms21.30 (1.04, 1.62)0.02Side effectsl胃肠道反应l耳毒性l皮疹l肝损害l听力减退 WHAT

14、 ELSE CAN WE LEARN死亡风险l两组全因死亡率(3% vs 4%，P=0.87)、呼吸系统疾病相关死亡率(2% vs 1%, P=0.48)、心血管疾病死亡率均无显著差异 (0.2%, P=1.00) Azithromycin for prevention of exacerbations of COPD. Albert, et al. N Engl J Med 2011, 365:689-698 l对照组死亡的风险是阿奇霉素治疗组的2.06倍 (p = 0.33) Long-term azithromycin use in patients with chronic obstr

15、uctive pulmonary disease and tracheostomy Blasi, et al. Pulmonary Pharmacology & Therapeutics 23 (2010) 200207Long-term azithromycin use in patients with chronic obstructive pulmonary disease and tracheostomy Blasi, et al. Pulmonary Pharmacology & Therapeutics 23 (2010) 200207长期口服阿奇霉素显著改善气管切

16、开的COPD患者的生活质量（MRF26）lLife qualityAzithromycin for prevention of exacerbations of COPD Albert, et al. N Engl J Med 2011, 365:689-698. l Life quality谁 能 受 益？Albert, et al. N Engl J Med 2011, 365:689-698. Azithromycin for prevention of exacerbations of COPD The effect of oral clarithromycin on health s

17、tatus and sputum bacteriology in stable COPD Banerjee， et al. Respir Med 2005;99:208215.口服克拉霉素3个月对细菌定植无影响lSputum Bacteriology Azithromycin for prevention of exacerbations of COPD Albert, et al. N Engl J Med 2011, 365:689-698. 长期口服阿奇霉素患者细菌定植率下降，耐药率增加Macrolide Therapy in Adults and Children with Non-

18、Cystic Fibrosis Bronchiectasisl9 篇研究l成人6篇l儿童3篇l559例患者Clinical characteristics of the 9 trialsSourceTotal /Treated subjects (n)Therapy strategyDoseControlCourseKoh 199725/13Roxithromycin 4mg/kg,bidplacebo12wksTsang 199921/11Erythromycin 500mg,bidplacebo8wksCymbala 200522/11Azithromycin 500mg,2/wcrossover6msWong 2012141/71Azithr